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7o0l

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'''Unreleased structure'''
 
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The entry 7o0l is ON HOLD
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==Crystal structure of the human METTL3-METTL14 complex bound to Compound 8 (ADO_AC_093)==
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<StructureSection load='7o0l' size='340' side='right'caption='[[7o0l]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[7o0l]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7O0L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7O0L FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=UXW:4-[6-[(4,4-dimethylpiperidin-1-yl)methyl]pyridin-3-yl]-9-[6-[(phenylmethyl)amino]pyrimidin-4-yl]-1,4,9-triazaspiro[5.5]undecan-2-one'>UXW</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7o0l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7o0l OCA], [https://pdbe.org/7o0l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7o0l RCSB], [https://www.ebi.ac.uk/pdbsum/7o0l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7o0l ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/MET14_HUMAN MET14_HUMAN] N6-methyltransferase that methylates adenosine residues of some mRNAs and acts as a regulator of the circadian clock and differentiation of embryonic stem cells. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing and mRNA stability (PubMed:24316715, PubMed:24407421, PubMed:25719671). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop. M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization (By similarity).[UniProtKB:Q3UIK4]<ref>PMID:24316715</ref> <ref>PMID:24407421</ref> <ref>PMID:25719671</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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N(6)-methyladenosine (m(6)A) is the most frequent of the 160 RNA modifications reported so far. Accumulating evidence suggests that the METTL3/METTL14 protein complex, part of the m(6)A regulation machinery, is a key player in a variety of diseases including several types of cancer, type 2 diabetes, and viral infections. Here we report on a protein crystallography-based medicinal chemistry optimization of a METTL3 hit compound that has resulted in a 1400-fold potency improvement (IC(50) of 5 nM for the lead compound 22 (UZH2) in a time-resolved Forster resonance energy transfer (TR-FRET) assay). The series has favorable ADME properties as physicochemical characteristics were taken into account during hit optimization. UZH2 shows target engagement in cells and is able to reduce the m(6)A/A level of polyadenylated RNA in MOLM-13 (acute myeloid leukemia) and PC-3 (prostate cancer) cell lines.
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Authors: Bedi, R.K., Dolbois, A., Caflisch, A.
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1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors.,Dolbois A, Bedi RK, Bochenkova E, Muller A, Moroz-Omori EV, Huang D, Caflisch A J Med Chem. 2021 Sep 9;64(17):12738-12760. doi: 10.1021/acs.jmedchem.1c00773. , Epub 2021 Aug 25. PMID:34431664<ref>PMID:34431664</ref>
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Description: Crystal structure of the human METTL3-METTL14 complex bound to Compound 8 (ADO_AC_093)
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Dolbois, A]]
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<div class="pdbe-citations 7o0l" style="background-color:#fffaf0;"></div>
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[[Category: Caflisch, A]]
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== References ==
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[[Category: Bedi, R.K]]
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Bedi RK]]
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[[Category: Caflisch A]]
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[[Category: Dolbois A]]

Current revision

Crystal structure of the human METTL3-METTL14 complex bound to Compound 8 (ADO_AC_093)

PDB ID 7o0l

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